Nectin-4, a new serological breast cancer marker, is a substrate for tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM-17.
Article Details
- CitationCopy to clipboard
Fabre-Lafay S, Garrido-Urbani S, Reymond N, Goncalves A, Dubreuil P, Lopez M
Nectin-4, a new serological breast cancer marker, is a substrate for tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM-17.
J Biol Chem. 2005 May 20;280(20):19543-50. doi: 10.1074/jbc.M410943200. Epub 2005 Mar 22.
- PubMed ID
- 15784625 [ View in PubMed]
- Abstract
Serum markers are extensively used in diagnostic and follow-up of cancer patients. We recently described Nectin-4, a 66-kDa adhesion molecule of the Nectin family, which is a valuable new histological and serological marker for breast carcinoma. In vivo, Nectin-4 is re-expressed in breast carcinoma, and a circulating form of Nectin-4 is detected in the sera of patients with metastatic breast cancer. In vitro, a soluble form of Nectin-4 is produced in the supernatant of breast tumor cell lines (S. Fabre-Lafay, C. Ginestier, S. Garrido-Urbani, C. Berruyer, R. Sauvan, N. Reymond, J. Adelaide, J. Geneix, P. Dubreuil, J. Jacquemier, D. Birnbaum, and M. Lopez, manuscript in preparation). We have investigated the mechanisms that regulate the production of this soluble form. It was found that the soluble form of Nectin-4 detected in the sera of patients and the supernatant of breast tumor cell lines share similar biochemical and immunological features. The soluble Nectin-4 form (43 kDa) is formed by the entire Nectin-4 ectodomain. Nectin-4 shedding is constitutive, strongly enhanced by 12-O-tetradecanoylphorbol-13-acetate activation, and reduced tumor necrosis factor-alpha protease inhibitor TAPI-1 or by the tissue inhibitor of metalloproteinase-3 (TIMP-3). TAPI-1 and TIMP-3 are inhibitors of the endoprotease tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM-17. Overexpression or small interfering RNA-mediated silencing of TACE enhanced or reduced Nectin-4 shedding, respectively. Nectin-4 is not shed when expressed in TACE-deficient fibroblasts. Interestingly, the active form of TACE is overexpressed in breast tumors and may indicate that TACE is responsible for Nectin-4 shedding not only in vitro but also in vivo.